What are the effects of testosterone injections on muscle mass, bone mineral density, and neurological function in an adult trans‑male?

Effects of Testosterone Injections in Trans-Males

Testosterone therapy in trans-males produces significant increases in muscle mass (approximately 10% gain in lean body mass), maintains or modestly improves bone mineral density, and induces structural and functional brain changes in areas related to self-perception and body awareness. 1, 2

Muscle Effects

Testosterone administration consistently produces robust anabolic effects on skeletal muscle in trans-males:

• Lean body mass increases by approximately 10% within the first year of treatment, with the most dramatic gains occurring in the first 3-6 months 1, 3
• Fat mass simultaneously decreases by approximately 10%, resulting in favorable body composition changes 1, 4
• Grip strength and overall muscle strength improve alongside the increase in muscle mass 1

Importantly, adequate muscle development can be achieved even with low-dose testosterone regimens (≤62.5 mg/week), though higher doses may accelerate initial muscle gains 5. The Endocrine Society guidelines recommend 75-100 mg testosterone enanthate or cypionate intramuscularly weekly, or 150-200 mg every 2 weeks, targeting mid-normal male testosterone ranges 6.

The mechanism involves testosterone's direct anabolic effects on muscle protein synthesis, enhanced by androgen receptor activation in muscle tissue 7. Initial muscle gains are most pronounced in individuals with lower baseline lean body mass 5.

Bone Effects

The skeletal response to testosterone in trans-males is generally favorable but more modest than muscle changes:

• Bone mineral density (BMD) is maintained or shows small increases, particularly at the hip (approximately 7-8% increase over 2 years at the femoral neck) 8
• Spine BMD shows smaller, often non-significant increases (approximately 3% over 2 years) 8
• Trabecular bone at the distal radius may show modest improvements 1
• Bone turnover markers increase significantly (both formation marker P1NP and resorption marker CTX), suggesting an anabolic remodeling process rather than bone loss 1

The bone-protective effects likely result from both direct testosterone action on bone and peripheral aromatization to estradiol 8. The increased bone turnover reflects active bone remodeling in response to increased mechanical loading from greater muscle mass, rather than pathological bone loss 1.

Critical monitoring point: Trans-males who discontinue testosterone after gonadectomy are at risk for bone loss and should have BMD assessed if risk factors for osteoporosis exist 9. The Endocrine Society recommends measuring BMD of the lumbar spine and femoral neck after 1-2 years of therapy in those with osteoporosis risk factors 6.

Neurological Effects

Testosterone produces measurable structural and functional brain changes in trans-males:

• Cortical thickness increases in the insular cortex, a region involved in body perception and self-awareness 2
• The medial prefrontal cortex (involved in self-referential thinking) shows pre-existing differences that persist with treatment 2
• Functional connectivity increases between brain regions involved in self-perception, particularly between the medial prefrontal cortex and temporo-parietal junction 2
• White matter integrity improves, with increased fractional anisotropy in the fronto-occipital tract 2

These neurological changes align with improved quality of life and reduced gender dysphoria, though the guidelines note that cognitive function changes are inconsistent across studies 10.

Practical Implementation Algorithm

Dosing approach:

1. Start with testosterone enanthate or cypionate 75-100 mg IM weekly (or 150-200 mg every 2 weeks) 6
2. Alternative: testosterone undecanoate 1000 mg IM every 12 weeks after initial loading 1, 4
3. Target serum testosterone levels in the mid-normal male range (400-700 ng/dL measured midway between injections for short-acting esters) 6

Monitoring schedule:

• At 3 months: Assess symptom response, measure testosterone levels, check hematocrit, and evaluate for adverse effects 6
• Testosterone levels: Measure 2-3 months after initiation; for injectable esters, measure midway between injections. Adjust if >700 ng/dL or <350 ng/dL 6
• Hematocrit: Check at baseline, 3 months, then annually. Stop therapy if hematocrit >54% until it decreases, evaluate for sleep apnea, then reinitiate at reduced dose 6
• Annual monitoring: Complete blood count, liver function tests, lipid profile, blood pressure, and fasting glucose 9
• BMD: Consider at 1-2 years if osteoporosis risk factors present 6

Important Caveats

Common pitfall: The rapid increase in muscle mass and strength may outpace tendon and bone adaptation, potentially increasing injury risk during the first year of treatment 11. Advise gradual progression in physical activities and resistance training.

Metabolic considerations: Expect decreases in HDL cholesterol and increases in LDL cholesterol and triglycerides across all testosterone formulations 3, 4. These lipid changes require monitoring and management per standard cardiovascular risk guidelines 9.

Hematological effects: Hemoglobin and hematocrit increase significantly, with erythrocytosis being the most common dose-dependent adverse effect 6, 4. This is more pronounced with intramuscular formulations and higher doses.

Divergent evidence note: While older guidelines emphasized concerns about cardiovascular risk, more recent large observational studies and the TRAVERSE trial data suggest no increased cardiovascular mortality with appropriate monitoring 10. However, the TRAVERSE trial unexpectedly showed higher fracture rates in testosterone-treated men, though this was in older cisgender men with age-related hypogonadism, not trans-males 11.

Formulation differences: No clinically significant differences in muscle, bone, or safety outcomes exist between testosterone gel, patches, and injectable formulations in trans-males, though injections may produce more rapid initial muscle gains 3. Patient preference and cost often guide formulation choice 10.